Biology in the News Explained

Tumor evolution and chemotherapy resistance

Having spent the last two articles explaining why chemotherapy as currently practiced is a terrible way to treat metastatic cancer (if the goal is cure or even just life extension) it’s time to pivot a bit and explain that while standard chemotherapy “best practices” are completely the wrong approach for the majority of cancer patients, chemo drugs can still have some valuable utility, especially as part of a multifaceted treatment, if doctors applied scientific knowledge from other fields to their understanding of why even effective chemo drugs nearly always become eventually useless in the same patient.

While any oncologist is familiar with the problem of acquired resistance to previously effective chemo drugs, it seems that the field of clinical oncology as a whole has failed both to examine carefully the mechanisms for this or to explore possible methods to overcome or delay resistance (other than by the ultimately useless blunt instrument of switching drugs), in order to extend meaningful life in metastatic patients.

There are two important facets to this failure. The first, briefly, is cultural. Our society’s Cancer Machine has an odd, collective cognitive dissonance in which the idea of “curing” late-stage patients, understood rationally to be nearly impossible, exists alongside treatment techniques theoretically designed to cure, but which never have come close to this ideal. (This dovetails with the other cognitively dissonant dichotomy in which the continued propaganda of “cure” overlays the fear of cancer as inevitable death in early-stage patients.) So doctors, particularly specialists such as surgeons and radiologists treating one part of the body, often imply that the goal of a given treatment is cure, even while their own data show that cure is essentially never achieved by their treatments.

But the focus of the discussion here is the science of tumors:  their heterogeneity and ability to evolve, which oncologists again understand in the abstract, but generally fail to respond to, because they do not seem to understand evolutionary biology. This is not for lack of researchers encouraging the approach to tumors in these terms (Gerlinger and Swanton 2012; Greaves and Maley 2012; Marusyk et al 2012). And it’s not doctors’ fault that medical schools that their training does not include the basic principles of evolution and population biology (although in the case of oncologists at least, it clearly should).

Here is an oversimplification of the essential problem (for more nuances and explanations showing how much more complicated it actually is, see the references below): malignant tumors are heterogeneous populations of cells which actually compete with each other for resources. Tumor cells are mutating all the time, via several mechanisms such as drift and varying selection pressures, which include exposure to different chemical microenvironments, oxygen levels, etc. (which can even be different in different parts of the same tumor, not just between different tumors).

Although there are many selective pressures driving tumor evolution that we have no known control over, the use of chemotherapy is a big one that we do. That is, our misuse of chemotherapy for cancer treatment is similar to the misuse of pesticides in agriculture. In the latter case we create resistant pests by imposing a strong selection pressure on a heterogeneous population of insects, most of which are susceptible to the poison but a few of which by chance are resistant. Once all the susceptible individuals are destroyed, the resistant ones have no competition and can take over, and the pesticide is now useless.

In a way, chemotherapy is even more insidious because of the evidence that chemo itself increases the mutation rate of cancer cells, which is abnormally high. The implications of this should be sobering: misuse of chemo drugs can actually hasten the evolution of one’s tumors to a more aggressive form (although it has been argued that the changes occur more on a phenotypic than genotypic level [Germain, 2012]). In any case, the end result is that the current paradigm of chemotherapy treatment, the delivery of “highest tolerated dose” (HTD), while intended to circumvent resistance by the use of overwhelming force (as the use of high levels of antibiotics for ten days to two weeks wipes out an infection so that it will not return), in reality almost never works, mainly because the levels of drugs truly needed to wipe out all populations of cancer cells would be much too high for the patient to survive. So, we continue to deliver drugs at a sublethal level which promotes resistance, and probably shortens lifespan much more often than currently acknowledged. The effects of even those drugs identified in trials as providing “complete response” for some patients are nearly always only temporary, and extend life in many cases by less than a year, by which time resistant (untreatable) tumors come roaring back (the dreaded “progressive disease”), ultimately killing the patient for whom there are no more treatment options.

There is already a fairly rich literature on the mechanisms of the evolution of resistance in tumors, although ideas to overcome it are still largely theoretical and remain untested. One study, however, provides not only a model for how resistance could possibly be overcome, but tests the model successfully in mice in a laboratory setting, with a quite intriguing result. Gatenby et al. (2009) developed a mathematical model that showed that it should be possible to maintain a low tumor burden with a single effective chemo drug, by continually adjusting the rate and levels (and thus the selective pressure on the tumor cell population) at which the drug is delivered.  The key to the new paradigm is that it does not aim for a cure, but rather management of tumors at a non-life-threatening level. To shift to such a paradigm would not be unreasonable scientifically, since cure of metastatic disease via conventional treatments is essentially nonexistent (no matter how much we pretend it is not). The authors find that lifespan can be extended indefinitely by using this protocol that is individualized to how the patient’s tumors are responding to the drug.

The important assumption of the model is that resistance implies a metabolic cost, which allows susceptible cells to outcompete resistant cells in the absence of the selective chemo agent. While this may not necessarily be true for all forms of resistance (Germain, 2012) there is a lot of evidence that it is much of the time (including from Gatenby et al.’s subsequent laboratory experiment). Given that assumption, chemotherapy treatments are adjusted downward when there is a strong response from a tumor — i.e., when the tumor shrinks quickly as the majority population of susceptible cells is killed. This allows susceptible cells to remain and continue to compete with resistant cells, keeping them suppressed to a relatively small population size.

What strengthens Gatenby et al.’s paper is that they followed up their mathematical model with an in vivo mouse study, testing the model’s predictions. Human tumors implanted in mice are convenient for this purpose because they can be measured easily (see picture). In the authors’ treatment group, tumors were measured and the chemotherapy dose adjusted, while for comparison a group of mice was administered the typical static dose of the same chemo drug, regardless of tumor size. Not only was a low tumor burden maintained in the dynamically treated mice (which resulted in a greatly increased lifespan), but the amount of the drug required to maintain the tumors at a low level dropped to 17% of the normally administered levels of the drug, suggesting that much lower toxicities are needed under this protocol. In other words, it’s a win-win: longer life at a higher quality. The only thing that is being given up in return is the misguided hope for a cure that does not exist anyway.

The time when cancer for many more people can be managed as a chronic disease is thus possible with the tools we already have. This pre-clinical result needs to be followed up with human data, in order to establish how to make such a protocol work in a situation where the tumors cannot be so easily measured with a pair of calipers. Refining this will clearly take time, given all the permutations of cancers and drugs, but now is the time to start, and no doubt there are many stage IV patients who would be willing to try something different from the hopeless alternative. What is clear is that for all the reasons stated here and in the last post, standard chemotherapy regimens for metastatic patients are clearly not only a waste of time, but worse, are killing a lot of us more quickly and miserably than if we just died of our cancer.

There’s no need to throw out the chemo baby with the bathwater, as shown by this paper; we just need to be a lot more intelligent with its use, and that will start by cancer doctors listening to what evolutionary biologists have to offer in their understanding of tumor biology.

 

References

Gatenby RA, Silva AS, Gillies RJ, Frieden BR, 2009. Adaptive therapy. Cancer Res. 69(11):4894-903. doi: 10.1158/0008-5472.CAN-08-3658.

Gerlinger M, Swanton C 2012. How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine. Br J Cancer. 103(8):1139-43. doi: 10.1038/sj.bjc.6605912. Epub 2010 Sep 28.

Germain, P-L., 2012. Cancer cells and adaptive explanations. Biology & Philosophy 27(6):785-810.

Greaves M, Maley CC 2012. Clonal evolution in cancer. Nature. 481(7381):306-13. doi: 10.1038/nature10762.

Marusyk A, Almendro V, Polyak K 2012. Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer. 12(5):323-34. doi: 10.1038/nrc3261.

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5 Responses to “Tumor evolution and chemotherapy resistance”

  1. Elaine LaMonk says:

    I would really like to hear about your personal treatment plan. I was diagnosed three years ago with PPC IIIC and BRCA2+. I’m on my third chemo protocol.

    Elaine

  2. Elaine,
    The key to it is to figure out what works for you. Essentially, it’s the one-size-fits-all standard of care that is not working — anyone can see that who pays attention to what happens to anyone they know whose cancer metastasizes. The fundamental necessity is to figure out how to monitor what’s going on with your cancer as continuously as possible. I find that oncologists go on and on about how tumor markers really aren’t that helpful, and there’s no point in getting scans less than three months apart, but the problem is they only think statistically and both of these statements are completely untrue for me. My tumor markers have been a very reliable indicator of what’s going on with my tumors, so now I get them every two weeks. As far as scans go, MRIs don’t add to one’s radiation load, so I have been doing them every month as I experiment with various treatments in different combinations, to give added information to the tumor markers. (Caveat – MRIs are good at seeing tumors in livers, but not in other soft organ tissue, so they don’t work for everyone.)

    Once you have established regular monitoring of your data, you can start to figure out what’s working. I am very lucky in that the oral drug Xeloda works well for me so far, but that I have to manage its use very carefully to delay resistance as long as possible (as per the article above). I also know that my only chance for longer term cancer suppression is through my immune system (please see the last several posts on this blog for more detail about that), so I have very strict criteria about further chemo use (I’ve done the usual thing twice before, with the unsurprising result that I still have metastatic cancer), in that it cannot suppress my immune system. For me, that also leaves directed liver treatment (TACE) as an option and I am trying to use that for management as well (with three different drugs that are different from 5-fluorouracil, the active agent from Xeloda). I am doing active immunotherapy in Germany because unfortunately what they do is unavailable here. I also am in the process of experimenting with various hormonal options – i.e. most people know about tamoxifen and aromatase inhibitors, but other hormonal drugs that have shown good promise for tumor stability are Affinitor and Faslodex, and another possibility is entzulatimide (Xtandi) which was approved last summer for prostate cancer patients, and is currently being tested in breast cancer patients whose tumors are at least 10% androgen positive (if you’ve had a biopsy you can ask that the tissue be tested for androgen sensitivity just as it was already tested for estrogen sensitivity) – so it’s available but would have to be prescribed off-label.

    What I know for sure at this point is that Xeloda has been the most effective treatment for me. All the other stuff is designed to help prevent resistance to Xeloda by 1) attacking totally different pathways in the cancer cells, because that makes it much harder for them to develop resistance to a particular agent and 2) creating enough stability (at least) so that I can go off Xeloda for at least a couple months at a time every now and then. The other treatments are primarily designed to give me space to do that, rather than necessarily be tumor-shrinkers as well.

    I can’t really speak to actual results yet, mainly because I didn’t actively focus on this particular plan until this past winter, when I realized I was tired of lurching from crisis to crisis when a particular treatment seemed to work for awhile but then the tumors came roaring back anyway (still, I’ve had liver tumors for over 2 years now and they are still under control). Digging through the cancer literature has convinced me more and more that the oncological community is utterly clueless and nonsensical about the way cancer treatment is approached, and there’s no doubt that much of it is driven by financial incentives. I’m not saying at all that doctors don’t care about their patients, but all the recent healthcare reforms have revealed absolutely that the wrong incentive structures increase costs and worsen outcomes for patients. For example, people finally realized that Medicare reimbursements to hospitals actually incentivized re-admissions to hospitals as a result of complications or failure of treatments. When that monetary incentive is taken away, re-admits drop and money is saved, and patients are healthier. It’s simply an emergent property of the system. And the fact is that the way chemo is administered, using “maximum tolerated dose” on people for whom they haven’t even bothered to figure out whether a particular drug will work, maximizes profits for pharmaceutical companies and probably oncologists, while also maximizing the probability of resistance, quickly. The two most important things we could be doing now for metastatic cancer patients, i.e. 1) identifying ahead of time which drugs are most likely to work and 2) adjusting dosage based on response to maximize healthy lifespan, will lose the industry money (at least in the short term).

    What I write is all simply about common biological sense apart from the monetary issue, and what this post boils down to is that if oncologists truly understood the basics of evolution, they too would see that much of the time, standard chemo treatments are in all likelihood killing a lot of people sooner than the cancer would if left alone, and certainly they are ruining quality of life in (all too often) the few months people have left.

    It’s clear that there are extremely aggressive cancers that a management approach would not help with. But it’s also true that current treatment doesn’t help people with those either, so as far as those cases go, people are simply and sadly out of luck (until we get proper immune therapies online, at least). Then of course there are the many cancers that we find at screening but would never have metastasized, i.e. would not kill anyone. We count those people as “lives saved by treatment” when they would be better categorized as “lives upheaved by unnecessary treatment.” (That’s another topic that I also have covered on this blog, if you look through the cancer archives). I think most of us with cancer are somewhere in the middle, in a situation that if we approached the disease intelligently, it could be managed for years longer than people are living now, similar to those with diabetes or heart disease. At this point I have no idea how well this will work for me because no one I know is done it before – I’m figuring it all out on my own, and n=1. There are so many unknowns and stuff out of my control because of the horrid mutation rate and adaptations that cancer shows, and the fact that so little pathology is conducted after a biopsy. But I know that piling on with a single chemo drug at the maximum dose is completely the wrong thing to do, so all I can do is my best guess at the alternative, and keep writing about this stuff as I learn, so that hopefully other patients will start considering it too, and not just keep accepting the crazy irrational paradigm we are currently stuck with. Patients need to be the ones to demand better, because the oncological community is simply stuck where it’s been for decades, and with all the money being poured into cancer, we should be way beyond where we are – but I believe it’s the huge amount of money involved that has kept us in this holding pattern for so long, to the point where we have been trained just to accept it as the “way things are” instead of realizing that a better way is possible right now.

    Good luck to you.

  3. Ana says:

    Hi
    I do not have cancer by I am an avid reader of biology books and user of herbs to treat me when sick.
    Last week from nowhere I got a 39/40 celcius fever for 2 days.
    My body temperature in normally 35
    As fever is a natural response from the body to kill somekind of abnormall invasion I lead myself to a higher fever to help the body in this immune system process.
    I also drink lots of water and simple soups and nothing else. And try to sleep the whole time.In 48h this is usually resolved and my body gets back to normal and then i start chewing fresh ginger for the next 3 or 4 days as I begin to eat normally.
    Sometimes I also use bromelein extract.
    I am 39 and doing this since i can remember. Same for my 2 kids- i let fever go up but not so high and lots of sleep. And they are the most healthy in the school.
    Of course i make exceptions – well once – when one of them got a very bad ear infection. But i made herbsleep and controled the fever the same. I do not mix antibiotics with pain reliefers so she only got the minimum antibiotic possible.

    My point…why not a similar approach to cancer? Help the immune system resolve the issue by helping it ?

  4. Ana says:

    Ps and adding also yogurt with live cultures and taking out sugar from diet when sick

  5. Ana, you are generally right about the importance of the immune system. I have touched on this in a couple previous posts — for example, see this one on why chemotherapy is ultimately a bad way to treat cancer — and I plan on going into more detail on this in future posts. Thanks for reading.

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